Nicotinamide riboside and pterostilbene compositions and methods for treatment of neurodegenerative disorders

ABSTRACT

Compositions containing a combination of nicotinamide riboside and pterostilbene for treating neurodegenerative disorders, and methods of treating neurodegenerative disorders using these compositions and their equivalents are described. The neurodegenerative disorders that can be treated using these compositions or methods can include parkinson&#39;s disease, huntington&#39;s disease, alzheimer&#39;s disease, and the like. In an embodiment, the compositions containing a combination of nicotinamide riboside and pterostilbene can be prepared as oral formulations. In some embodiments, a dietary supplement comprises nicotinamide riboside and/or pterostilbene or equivalents.

RELATED APPLICATIONS

This application is a § 371 national-stage application based onPCT/US17/47979, filed Aug. 22, 2017, which claims the benefit ofpriority to U.S. Provisional Patent Application Ser. No. 62/378,053,filed Aug. 22, 2016, each of which is incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The field of the invention generally relates to compositions and methodsfor the treatment of neurodegenerative disorders. Embodiments of theinvention relate to nicotinamide riboside and pterostilbene compositionsand methods for treatment of neurodegenerative disorders.

BACKGROUND OF THE INVENTION

Neurodegenerative disorders are prevalent and can often produce symptomsthat greatly inhibit those with the disorder. Neurodegenerativedisorders manifest themselves in many ways but often produce symptomssuch as tremors, altered posture, dementia, memory loss, and speechproblems. Often, neurodegenerative disorders produce impaired motorcapabilities. Certain disorders can be hereditary or caused byenvironmental factors. Certain disorders such as Parkinson's disease maybe caused by prions.

Prior art treatments of these neurodegenerative disorders have failed totreat the disorder or adequately alleviate the symptoms. For example,reducing the death of dopaminergic neurons can maintain the body'snatural production of dopamine, which plays an important role in motorfunctions along with feelings of gratification. Certain disorders suchas Parkinson's disease have relied on treatments of administration ofLevodopa (L-DOPA), which is a precursor to dopamine and increases thedopamine concentration in the human brain.

Seven mammalian sirtuin enzymes, SIRT1-7, play an important role inmaintaining metabolic homeostasis in multiple tissues. SIRT1-7 exhibitdistinctive enzymatic activities, tissue and subcellular localization,and have been characterized as antiaging proteins. The sirtuins functionby translating changes in nutritional state to metabolic adaptations.

Sirtuin 1, (SIRT1), is a nicotinamide adenine dinucleotide (NAD+)dependent deacetylase. SIRT1 mediates p53 dependent processes,transcription regulation, muscle differentiation, adipogenesis, andprotection of neurons and their axons from degeneration. SIRT1 alsoparticipates in early embryogenesis, neurogenesis, and cardiogenesis.

Sirtuin 2 (SIRT2) is an evolutionarily conserved NAD+ dependent histone/protein deacetylase that tightly couples the cleavage of NAD+ andthe deacetylation of protein substrates.

Without being hound by theory, sirtuin enzymes are believed to act bytransferring an acetyl group from their substrate protein to theADP-ribose moiety of NAD+. It is believed this cleaves the coenzyme andreleases nicotinamide and O-acetyl-ADP-ribose. The mechanism of actionof sirtuins appears to involve regulating transcription throughdeacetylating histones and altering nucleosome structure. It is alsobelieved that non-histone proteins can be deacetylated by sirtuins. NAD+is an important cofactor regulating metabolic homeostasis and believedto be a rate-limiting substrate for sirtuin deacetylases. Prior arttreatments for certain neurodegenerative disorders includesadministering medications and surgery, but these have only reduced somesymptoms. Prior art treatments have failed to produce adequatebeneficial results for neurodegenerative disorders, and needs exist forimproved treatments for neurodegenerative disorders and/or symptoms ofneurodegenerative disorders. While the body's homeostatic levels of NAD+are generally stable, we have found that levels can be increased byproviding supplementation of NAD+ via NAD+ precursors over what would beexpected in the diet. Accordingly, embodiments of the invention andclaims are intended to provide NAD+ precursors and/or sirtuin activatorsas a supplement or an active pharmaceutical ingredient and not as anormal food. The addition of NAD+ precursors to amounts that canincrease the level of NAD+ in the body, certain tissues, or cellularcompartmentalization can lead to beneficial effects over the amountnormally consumed or located in these structures.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are methods and compositions related to treating and/orpreventing a neurodegenerative disease or disorder and/or slowing theprogression of a neurodegenerative disease or disorder in a subject byadministering to the subject (e.g., orally administering to the subject)a composition comprising a compound of Formula I or Formula II (e.g.,nicotinamide riboside), and/or a compound of Formula III (e.g.,pterostilbene). The neurodegenerative disease or disorder may beAlzheimer's disease, Huntington's disease, Parkinson's disease,dementia, diabetes, or a disease or disorder associated with aging.

In certain aspects, the methods and compositions provided herein relateto treating and/or preventing Alzheimer's disease in a subject byadministering to the subject (e.g., orally administering to the subject)a composition comprising a compound of Formula I or Formula II (e.g.,nicotinamide riboside) and/or a compound of Formula III (e.g.,pterostilbene).

In certain aspects, the methods and compositions provided herein relateto treating and/or preventing Huntington's disease in a subject byadministering to the subject (e.g., orally administering to the subject)a composition comprising a compound of Formula I or Formula II (e.g.,nicotinamide riboside) and/or a compound of Formula III (e.g.,pterostilbene).

In certain aspects, the methods and compositions provided herein relateto treating and/or preventing Parkinson's disease in a subject byadministering to the subject (e.g., orally administering to the subject)a composition comprising a compound of Formula I or Formula II (e.g.,nicotinamide riboside) and/or a compound of Formula III (e.g.,pterostilbene). Also provided herein are methods of treating, reducingthe risk of, and/or reducing the prevalence of indicia (e.g., indiciadisclosed herein) of a neurodegenerative disease in a subject byadministering to the subject (e.g., orally administering to the subject)a composition comprising a compound of Formula I or Formula II (e.g.,nicotinamide riboside) and/or a compound of Formula III (e.g.,pterostilbene). Indicia of neurodegenerative disease may be tremors,resting tremors, bradykinesia, NAD+ content, sirtuin activity, limbrigidity, Lewy bodies, postural instability, freezing of gait,micrographia, reduced facial expression, uncontrolled movements,movement that is abnormally fast or slow, stooped posture, dystonia,impaired fine motor dexterity, impaired motor coordination, impairedgross motor coordination, decreased arm swing, akathisia, speechproblems, softness of voice or slurred speech, difficulty swallowing,sexual dysfunction, cramping, drooling, excess saliva, loss of sense ofsmell, constipation, REM behavior disorder, mood disorder, orthostatichypotension, sleep disturbances, vision problems, fatigue, loss ofenergy, depression, cognitive issues such as memory issues, slowedthinking, confusion, death of dopaminergic neurons, reduced dopamineconcentration, prion occurrence, or dementia.

In certain embodiments of the compositions and methods provided herein,the composition comprises a compound of Formula I or Formula II (e.g.,nicotinamide riboside) (e.g., at least 50 mg, at least 75 mg, at least100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg,at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, atleast 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, atleast 525 mg, at least 550 mg, at least 575 mg, at least 600 mg, atleast 625 mg, at least 650 mg, at least 675 mg, at least 700 mg, atleast 725 mg, at least 750 mg, at least 775 mg, at least 800 mg, atleast 825 mg, at least 850 mg, at least 875 mg, at least 900 mg, atleast 925 mg, at least 950 mg, at least 975 mg, at least 1000 mg, atleast 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, atleast 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, atleast 1450 mg, or at least 1500 mg, of a compound of Formula I orFormula II (e.g., nicotinamide riboside)). In some embodiments, thecomposition comprises a compound of Formula III (e.g., pterostilbene)(e.g., at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg,at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg,at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least100 mg, at least 125 mg, at least 150 mg, at least 200 mg, at least 225mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg,at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, atleast 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, atleast 550 mg, at least 575 mg, at least 600 mg, at least 650 mg, atleast 675 mg, at least 700 mg, at least 725 mg, at least 750 mg, atleast 775 mg, at least 800 mg, at least 825 mg, at least 850 mg, atleast 875 mg, at least 900 mg, at least 925 mg, at least 950 mg, atleast 975 mg, or at least 1000 mg of a compound of Formula III (e.g.,pterostilbene)). In certain embodiments, the composition comprises botha compound of Formula I or Formula II (e.g., nicotinamide riboside)(e.g., at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg,at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, atleast 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, atleast 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, atleast 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, atleast 550 mg, at least 575 mg, at least 600 mg, at least 650 mg, atleast 675 mg, at least 700 mg, at least 725 mg, at least 750 mg, atleast 775 mg, at least 800 mg, at least 825 mg, at least 850 mg, atleast 875 mg, at least 900 mg, at least 925 mg, at least 950 mg, atleast 975 mg, at least 1000 mg, at least 1050 mg, at least 1100 mg, atleast 1150 mg, at least 1200 mg, at least 1250 mg, at least 1300 mg, atleast 1350 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mgof a compound of Formula I or Formula II (e.g., nicotinamide riboside))and a compound of Formula III (e.g., pterostilbene) (e.g., at least 15mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, atleast 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, atleast 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least125 mg, at least 150 mg, at least 200 mg, at least 225 mg, at least 250mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg,at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, atleast 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, atleast 575 mg, at least 600 mg, at least 650 mg, at least 675 mg, atleast 700 mg, at least 725 mg, at least 750 mg, at least 775 mg, atleast 800 mg, at least 825 mg, at least 850 mg, at least 875 mg, atleast 900 mg, at least 925 mg, at least 950 mg, at least 975 mg, or atleast 1000 mg of a compound of Formula III (e.g., pterostilbene)).

In certain embodiments, the method comprises administering a pluralityof doses of the composition. In some embodiments, at least 7 doses ofthe composition are administered. In some embodiments, at least 30 dosesof the composition are administered. In some embodiments, at least 60 ormore doses of the composition are administered. In some embodiments,each dose comprises at least 50 mg, at least 75 mg, at least 100 mg, atleast 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, atleast 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, atleast 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, atleast 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, atleast 525 mg, at least 550 mg, at least 575 mg, at least 600 mg, atleast 650 mg, at least 675 mg, at least 700 mg, at least 725 mg, atleast 750 mg, at least 775 mg, at least 800 mg, at least 825 mg, atleast 850 mg, at least 875 mg, at least 900 mg, at least 925 mg, atleast 950 mg, at least 975 mg, at least 1000 mg, at least 1050 mg, atleast 1100 mg, at least 1150 mg, at least 1200 mg, at least 1250 mg, atleast 1300 mg, at least 1350 mg, at least 1400 mg, at least 1450 mg, orat least 1500 mg of a compound of Formula I or Formula II (e.g.,nicotinamide riboside). In some embodiments, each dose comprises atleast 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, atleast 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, atleast 125 mg, at least 150 mg, at least 200 mg, at least 225 mg, atleast 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, atleast 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, atleast 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, atleast 550 mg, at least 575 mg, at least 600 mg, at least 650 mg, atleast 675 mg, at least 700 mg, at least 725 mg, at least 750 mg, atleast 775 mg, at least 800 mg, at least 825 mg, at least 850 mg, atleast 875 mg, at least 900 mg, at least 925 mg, at least 950 mg, atleast 975 mg, or at least 1000 mg of a compound of Formula III (e.g.,pterostilbene).

In certain embodiments, each dose comprises at least 50 mg, at least 75mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg,at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, atleast 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, atleast 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, atleast 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, atleast 600 mg, at least 650 mg, at least 675 mg, at least 700 mg, atleast 725 mg, at least 750 mg, at least 775 mg, at least 800 mg, atleast 825 mg, at least 850 mg, at least 875 mg, at least 900 mg, atleast 925 mg, at least 950 mg, at least 975 mg, at least 1000 mg, atleast 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, atleast 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, atleast 1450 mg, or at least 1500 mg of a compound of Formula I or FormulaII (e.g., nicotinamide riboside) and at least 15 mg, at least 20 mg, atleast 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, atleast 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90mg, at least 95 mg, at least 100 mg, at least 125 mg, at least 150 mg,at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, atleast 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, atleast 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, atleast 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, atleast 600 mg, at least 650 mg, at least 675 mg, at least 700 mg, atleast 725 mg, at least 750 mg, at least 775 mg, at least 800 mg, atleast 825 mg, at least 850 mg, at least 875 mg, at least 900 mg, atleast 925 mg, at least 950 mg, at least 975 mg, or at least 1000 mg of acompound of Formula III (e.g., pterostilbene).

In certain embodiments, a dose of the composition is administered atregular intervals over a period of time. In some embodiments, a dose ofthe composition is administered at least once a week. In someembodiments, a dose of the composition is administered at least twice aweek. In certain embodiments, a dose of the composition is administeredat least three times a week. In some embodiments, a dose of thecomposition is administered at least once a day. In some embodiments, adose of the composition is administered at least twice a day. In someembodiments, doses of the composition are administered for at least 1week, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks,for at least 1 month, for at least 2 months, for at least 3 months, forat least 4 months, for at least 5 months, for at least 6 months, or forat least 1 year. In some embodiments, administration of the compositioncomprises administration of the composition in one or more dose(s). Insome embodiments, administration of the composition comprisesadministration of the composition in one or more, five or more, ten ormore, twenty or more, thirty or more, forty or more, fifty or more, onehundred or more, or one thousand or more dose(s). The compositionsdisclosed herein may be administered over any period of time effectiveto achieve the desired therapeutic response for a particular patient,composition, and mode of administration, without being toxic to thepatient. The period of time may be at least 1 day, at least 10 days, atleast 20 days, at least 30, days, at least 60 days, at least threemonths, at least six months, at least a year, at least three years, atleast five years, or at least ten years. The dose may be administeredwhen needed, sporadically, or at regular intervals. For example, thedose may be administered monthly, weekly, biweekly, triweekly, once aday, or twice a day.

In certain embodiments, the composition is formulated for oral delivery.In some embodiments, the composition is formulated as a pill, a tablet,or a capsule. In some embodiments, the composition is administeredorally. In certain embodiments, the composition is self-administered.

Some embodiments may include a composition comprising a combination of atherapeutically effective amount of nicotinamide riboside and atherapeutically effective amount of pterostilbene; and apharmaceutically acceptable excipient, wherein the combination is in atherapeutically effective amount for treatment of a neurodegenerativedisorder.

Certain embodiments may include a method comprising administering acombination of a therapeutically effective amount of nicotinamideriboside and a therapeutically effective amount of pterostilbene fortreatment of a neurodegenerative disorder in a patient in need oftreatment thereof. In many cases, a precursor of nicotinamide ribosidecan be used to create a therapeutically effective amount of nicotinamideriboside. In some embodiments, a precursor of nicotinamide riboside canbe used to create an effective amount of nicotinamide riboside.

Some embodiments may include oral formulations and methods of treatingneurodegenerative disorders. In certain embodiments, a composition maycontain a therapeutically effective amount of nicotinamide riboside, atherapeutically effective amount of pterostilbene, or both. In certainembodiments, a composition may comprise nicotinamide riboside andpterostilbene. In certain embodiments, a method may includeadministering a therapeutically effective amount of nicotinamideriboside and/or pterostilbene. In certain embodiments, a method mayinclude orally administering a therapeutically effective amount of acombination of nicotinamide riboside and pterostilbene. In certainembodiments, a method may include orally administering a therapeuticallyeffective amount of a combination of nicotinamide riboside andpterostilbene to treat a neurodegenerative disorder.

In certain embodiments, a composition may contain a therapeuticallyeffective amount of nicotinamide riboside, a therapeutically effectiveamount of pterostilbene, or both. In certain embodiments, a method mayinclude administering an effective amount of nicotinamide ribosideand/or pterostilbene.

In certain embodiments, nicotinamide riboside may be administered in anamount of between about 100 mg and about 1000 mg per day. Nicotinamideriboside may be administered in combination with pterostilbene and saidpterostilbene may be administered in an amount of between about 25 mgand about 500 mg per day.

In certain embodiments, nicotinamide riboside may be administered in anamount of between about 200 mg and about 700 mg per day. Nicotinamideriboside may be administered in combination with pterostilbene and saidpterostilbene may be administered in an amount of between about 25 mgand about 250 mg per day.

In certain embodiments, nicotinamide riboside may be administered in anamount of about 250 mg per day. Nicotinamide riboside may beadministered in combination with pterostilbene and said pterostilbenemay be administered in an amount of between about 25 mg and about 250 mgper day. In certain embodiments, nicotinamide riboside may beadministered in an amount of about 250 mg per day. Nicotinamide ribosidemay be administered in combination with pterostilbene and saidpterostilbene may be administered in an amount of about 50 mg per day.

Certain embodiments may include administering a therapeuticallyeffective amount of nicotinamide riboside and/or pterostilbene toincrease a human's sirtuin activity. Certain embodiments may includeadministering a therapeutically effective amount of nicotinamideriboside and/or pterostilbene to increase a human's brain sirtuinactivity.

Certain embodiments may include administering a therapeuticallyeffective amount of nicotinamide riboside and/or pterostilbene toincrease cellular NAD+ concentration. Certain embodiments may includeadministering a therapeutically effective amount of nicotinamideriboside and/or pterostilbene to increase muscle NAD+ concentration.Certain embodiments may include administering a therapeuticallyeffective amount of nicotinamide riboside and/or pterostilbene toincrease brain NAD+ concentration. Certain embodiments may includeadministering a therapeutically effective amount of nicotinamideriboside and/or pterostilbene to increase mitochondrial NAD+concentration. Certain embodiments may include increasing NAD+concentration in a human.

Certain embodiments comprise a sirtuin activating composition whereinsaid composition may comprise a therapeutically effective amount ofnicotinamide riboside and/or pterostilbene.

Certain embodiments may include administering a therapeuticallyeffective amount of nicotinamide riboside and/or pterostilbene toincrease the uptake of certain neurotransmitters such as, but notlimited to, dopamine.

Certain embodiments may include administering an effective amount ofnicotinamide riboside and/or pterostilbene to maintain normal or healthycellular NAD+ concentration. Certain embodiments may includeadministering an effective amount of nicotinamide riboside and/orpterostilbene to maintain normal or healthy NAD+ concentration. Certainembodiments may include administering an effective amount ofnicotinamide riboside and/or pterostilbene to maintain normal or healthybrain NAD+ concentration. Certain embodiments may include administeringan effective amount of nicotinamide riboside and/or pterostilbene tomaintain normal or healthy mitochondrial NAD+ concentration. Certainembodiments may include increasing NAD+ concentration in a human.Certain embodiments may include maintaining a normal or healthy NAD+concentration in a human.

Certain embodiments comprise a sirtuin activating composition whereinsaid composition may comprise an effective amount of nicotinamideriboside and/or pterostilbene and said composition maintains a normal orhealthy level of sirtuin activity. Certain embodiments may includeincreasing sirtuin activity in a human. Certain embodiments may includemaintaining a normal or healthy sirtuin activity in a human.

Certain embodiments may include administering an effective amount ofnicotinamide riboside and/or pterostilbene to maintain a normal orhealthy uptake of certain neurotransmitters such as, but not limited to,dopamine. Certain embodiments may include increasing neurotransmitteruptake in a human. Certain embodiments may include maintaining a normalor healthy uptake of neurotransmitters in a human.

Certain embodiments comprise an effective amount of nicotinamideriboside and/or pterostilbene and said composition maintains a normal orhealthy level of cellular detoxification. Certain embodiments mayinclude increasing cellular detoxification in a human. Certainembodiments may include maintaining a normal or healthy cellulardetoxification in a human.

Some embodiments may include a composition comprising a therapeuticallyeffective amount of nicotinamide mononucleotide and a therapeuticallyeffective amount of epsilon-viniferin; and a pharmaceutically acceptableexcipient, wherein the composition is in a therapeutically effectiveamount for treatment of a neurodegenerative disorder.

Certain embodiments may include a method comprising administering atherapeutically effective amount of nicotinamide mononucleotide and atherapeutically effective amount of epsilon-viniferin for treatment of aneurodegenerative disorder in a patient in need of treatment thereof.

Certain embodiments may include a composition comprising atherapeutically effective amount of nicotinamide mononucleotide and atherapeutically effective amount of niacin; and a pharmaceuticallyacceptable excipient, wherein the composition is in a therapeuticallyeffective amount for treatment of a neurodegenerative disorder.

Some embodiments may include a method comprising administering atherapeutically effective amount of nicotinamide mononucleotide and atherapeutically effective amount of niacin for treatment of aneurodegenerative disorder in a patient in need of treatment thereof.

Some embodiments may include a composition comprising a therapeuticallyeffective amount of nicotinamide riboside and a therapeuticallyeffective amount of epsilon-viniferin; and a pharmaceutically acceptableexcipient, wherein the composition is in a therapeutically effectiveamount for treatment of a neurodegenerative disorder.

Some embodiments may include a method comprising administering atherapeutically effective amount of nicotinamide riboside and atherapeutically effective amount of epsilon-viniferin for treatment of aneurodegenerative disorder in a patient in need of treatment thereof.

Some embodiments may include a composition comprising a therapeuticallyeffective amount of nicotinamide riboside and a therapeuticallyeffective amount of resveratrol; and a pharmaceutically acceptableexcipient, wherein the composition is in a therapeutically effectiveamount for treatment of a neurodegenerative disorder.

Some embodiments may include a method comprising administering atherapeutically effective amount of nicotinamide riboside and atherapeutically effective amount of resveratrol for treatment of aneurodegenerative disorder in a patient in need of treatment thereof.

Some embodiment may include a composition as described herein used toregulate sirtuin deacetylase expression.

Certain embodiments may include a pharmaceutical composition comprisingnicotinamide riboside, pterostilbene or a combination thereof fortreating neurodegenerative disorders as described herein. In certainembodiments, the composition may comprise a therapeutically effectiveamount of nicotinamide riboside. In certain embodiments, the compositionmay comprise a therapeutically effective amount of pterostilbene. Incertain embodiments, the composition will be provided on consecutivedays and may be provided for at least a week, preferably at least twoweeks, and most preferably at least a month.

Certain embodiments may include a dietary supplement compositioncomprising nicotinamide riboside, pterostilbene or a combination thereoffor reducing the risk of neurodegenerative disorders as describedherein. Certain embodiments may include a dietary supplement compositioncomprising nicotinamide riboside, pterostilbene or a combination thereoffor reducing the risk of indicia of a neurodegenerative disorder asdescribed herein. In certain embodiments, the composition may comprisean effective amount of nicotinamide riboside. In certain embodiments,the composition may comprise an effective amount of pterostilbene. Incertain embodiments, the composition will be provided on consecutivedays and may be provided for at least a week, preferably at least twoweeks, and most preferably at least a month.

In certain embodiments, a composition as described herein can be usedfor diagnostic and/or predictive purposes. In such embodiments,differences in blood and/or brain NAD+ levels can be measured afteradministering compositions as described herein and comparing to knownNAD+ levels in patients exhibiting neurodegenerative disorders, whichcan be compared to baseline levels to be used for diagnostic and/orpredictive purposes. NAD+ brain levels can be measured via ³¹P magneticresonance spectroscopy.

In certain embodiments, a pharmaceutical composition may comprise atherapeutically effective amount of a combination of nicotinamideriboside and pterostilbene. A pharmaceutical composition can be in theform of a soft gel capsule or hard shell capsule, or other solid formsuch as a tablet. In certain embodiments, the pharmaceutical compositionmay contain about 250 mg of nicotinamide riboside and about 50 mg ofpterostilbene. A pharmaceutical composition can be administered one ormore times daily. In certain embodiments, the composition may beadministered twice daily. In some embodiments where the pharmaceuticalcomposition is administered twice daily, the composition may containabout 125 mg of nicotinamide riboside and about 25 mg of pterostilbene.In certain embodiments, the compounds, compositions or pharmaceuticalcompositions containing nicotinamide riboside and pterostilbene may beprepared as oral formulations.

Additional features, advantages, and embodiments of the invention areset forth or apparent from consideration of the following detaileddescription and claims. Moreover, it is to be understood that both theforegoing disclosure and the following description are exemplary andintended to provide further explanation without limiting the scope ofany invention as claimed.

I. Definitions

The terms “patient”, “subject”, “individual” or “host” refer to either ahuman or a non-human animal.

The terms “treating” and “improving” mean that a neurodegenerativedisorder and/or indicia of a neurodegenerative disorder is cured,lessened, reduced, improved, ameliorated, palliated, prevented, and/orreversed after administration. “Treating” and “improving” may also meanreducing the risk of indicia of a neurodegenerative disorder. “Treating”and “improving” may also mean reducing the risk of developing indicia ofa neurodegenerative disorder. Curing, lessening, reducing, improving,ameliorating, palliating, preventing, and/or reversing indicia of aneurodegenerative disorder can be considered achievement of a desiredtherapeutic effect, or a desired effect from a dietary supplement.Indicia of a neurodegenerative disorder may include tremors includingresting tremors, bradykinesia, NAD+ content such as but not limited tocellular NAD+ content, sirtuin activity, limb rigidity, Lewy bodies,postural instability, freezing of gait, micrographia, reduced facialexpression, uncontrolled movements including movement that is abnormallyfast or slow, stooped posture, dystonia, impaired fine motor dexterityand motor coordination, impaired gross motor coordination, decreased armswing, akathisia, speech problems, softness of voice or slurred speech,difficulty swallowing, sexual dysfunction, cramping, drooling, excesssaliva, loss of sense of smell, constipation, REM behavior disorder,mood disorder, orthostatic hypotension, sleep disturbances, visionproblems, fatigue, loss of energy, depression, cognitive issues such asmemory issues, slowed thinking, confusion, death of dopaminergicneurons, reduced dopamine concentration, prion occurrence, and dementia.“Treating”, “treatment”, ‘improving”, and “improvement” may be usedinterchangeably and their meaning as used herein will be clear to theskilled artisan. “Treating” and improving” may also refer to thereduction or elimination of other medication or medications administeredto a patient, wherein that medication or medications is intended tocure, lessen, reduce, improve, ameliorate, palliate, prevent, and/orreverse a neurodegenerative disorder or indicia of a neurodegenerativedisorder.

As used herein, the term “therapeutically effective” refers to theamount of nicotinamide riboside and/or pterostilbene or theirequivalents needed to produce a desired therapeutic result. In certainembodiments, nicotinamide mononucleotide, niacinamide, nicotinamide,nicotinic acid and/or niacin may be substituted for nicotinamideriboside. In certain embodiments, a combination of nicotinamideriboside, nicotinamide mononucleotide, and/or niacin may be used. Incertain embodiments epsilon-viniferin and/or resveratrol may besubstituted for pterostilbene. In certain embodiments, a combination ofpterostilbene, epsilon-viniferin, and/or resveratrol may be used.

As used herein, the term “effective” can refer to an amount ofnicotinamide riboside and/or pterostilbene or their equivalents neededto produce a desired result. In certain embodiments, an effective amountmay be an amount that achieves the result of maintaining a normal orhealthy level of indicia of a neurodegenerative disorder. In certainembodiments, an effective amount can refer to an amount of nicotinamideriboside and/or pterostilbene or their equivalents needed to reduce therisk of indicia of a neurodegenerative disorder. An “effective” amountcan also encompass a “therapeutically effective” amount depending uponthe particular composition. The meaning of these terms will be clear toone of ordinary skill in the art when considering the claims and thecontext in which they are used.

As used herein, the term “pharmaceutically acceptable carrier” refers toa pharmaceutically-acceptable material, composition or vehicle, such asa liquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting any subject compositionor component thereof.

As used herein, the term “acceptable carrier” can refer to an acceptablematerial, composition or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material, involved incarrying or transporting any subject composition or component thereof.

As used herein “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissues,organs, and/or bodily fluids of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problems orcomplications commensurate with a reasonable benefit/risk ratio.

“Stereoisomer”, as used herein, refers to isomeric molecules that havethe same molecular formula and sequence of bonded atoms (constitution),but which differ in the three dimensional orientations of their atoms inspace. Examples of stereoisomers include enantiomers and diastereomers.As used herein, an enantiomer refers to one of the two mirror-imageforms of an optically active or chiral molecule. A racemic mixturecontains both forms of the optically active or chiral molecule.Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers (non-superimposable mirror images of each other). Chiralmolecules contain a chiral center, also referred to as a stereocenter orstereogenic center, which is any point, though not necessarily an atom,in a molecule bearing groups such that an interchanging of any twogroups leads to a stereoisomer. In organic compounds, the chiral centeris typically a carbon atom, though it is also possible for other atomsto be stereocenters in organic and inorganic compounds. A molecule canhave multiple stereocenters, giving it many stereoisomers. In compoundswhose stereoisomerism is due to tetrahedral stereogenic centers (e.g.,tetrahedral carbon), the total number of hypothetically possiblestereoisomers will not exceed 2n, where n is the number of tetrahedralstereocenters. Molecules with symmetry frequently have fewer than themaximum possible number of stereoisomers. A mixture of enantiomers isreferred to as a racemic mixture; which is typically 50:50 but that candiffer due to the process of manufacture. A mixture of enantiomers canbe enantiomerically enriched so that one enantiomer is present in anamount greater than 50%. Enantiomers and/or diasteromers can be resolvedor separated using techniques known in the art.

“Substituted,” as used herein, refers to all permissible substituents ofthe compounds or functional groups described herein. The permissiblesubstituents can include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, but are notlimited to, halogens, hydroxyl groups, or any other organic groupingscontaining any number of carbon atoms, which may be 1-14 carbon atoms,and optionally include one or more heteroatoms such as oxygen, sulfur,or nitrogen grouping in linear, branched, or cyclic structural formats.Representative substituents include alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substitutedphenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio,phenylthio, substituted phenylthio, arylthio, substituted arylthio,cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl,carboxyl, substituted carboxyl, amino, substituted amino, amido,substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀cyclic, heterocyclic, substituted heterocyclic, amino acid,poly(lactic-co-glycolic acid), peptide, and polypeptide groups. Suchalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, sulfonyl, substitutedsulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl,substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, aminoacid, poly(lactic-co-glycolic acid), peptide, and polypeptide groups canbe further substituted.

Heteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valences of the heteroatoms. It is understood that“substitution” or “substituted” includes the implicit proviso that suchsubstitution is in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound, i.e., a compound that does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups.

The term “formulation” may be used interchangeably with “composition”“dietary supplement” and/or “active agent.” In certain embodiments,formulation may mean a combination of a composition and/or active agentand other aspects of embodiments described herein such as but notlimited excipients. In certain embodiments, formulation may mean acombination of a composition and/or dietary supplement and other aspectsof embodiments described herein such as but not limited acceptablecarriers. The meaning of these terms will be clear to the skilledartisan based upon the context and their usage in the claims.

The term “dietary supplement” refers to a product intended to supplementthe diet that comprises one or more dietary ingredients such as but notlimited to nicotinamide riboside and/or pterostilbene. A dietarysupplement is limited to products that are intended for ingestion intablet, capsule, powder, softgel, gelcap, liquid, or other form ofadministration as described herein, that are not represented asconventional food or as the sole item of a meal or of the diet, and thatare labeled as dietary supplements. In some embodiments a dietarysupplement may be a composition that is in addition to the human dietand said composition is administered as disclosed herein, is not anatural or conventional food, meat or food flavoring or extract, orpharmaceutical product and that achieves desired effects such asimproving the indicia of a neurodegenerative disorder.

In some embodiments, a straight chain or branched chain alkyl has 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chains,C₃-C₃₀ for branched chains), 20 or fewer, 15 or fewer, or 10 or fewer.Likewise, some cycloalkyls have from 3-10 carbon atoms in their ringstructure, and may have have 5, 6 or 7 carbons in the ring structure.The term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims can include both “unsubstitutedalkyls” and “substituted alkyls”, the latter of which refers to alkylmoieties having one or more substituents replacing a hydrogen on one ormore carbons of the hydrocarbon backbone. Such substituents include, butare not limited to, halogens (such as fluorine, chlorine, bromine, oriodine), hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl,or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or athioformate), alkoxyl, phosphoryl, phosphate, phosphonate, aphosphinate, amino, amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido,sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromaticmoiety, —NRR′, wherein R and R′ are independently hydrogen, alkyl, oraryl, and wherein the nitrogen atom is optionally quaternized; —SR,wherein R is hydrogen, alkyl, or aryl; —CN; —NO₂; —COOH; carboxylate;—COR, —COOR, or —CON(R)₂, wherein R is hydrogen, alkyl, or aryl; azide,aralkyl, alkoxyl, imino, phosphonate, phosphinate, silyl, ether,sulfonyl, sulfonamido, heterocyclyl, aromatic or heteroaromaticmoieties, haloalkyl (such as —CF₃, —CH₂—CF₃, —CCl₃); —CN; —NCOCOCH₂CH₂,—NCOCOCHCH; —NCS; and combinations thereof.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, or one to six carbon atoms in its backbone structure.Likewise, “lower alkenyl” and “lower alkynyl” have similar chainlengths. Throughout the application, alkyl groups may be lower alkyls.In some embodiments, a substituent designated herein as alkyl is a loweralkyl.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude halogen, hydroxy, nitro, thiols, amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, aswell as ethers, alkylthios, carbonyls (including ketones, aldehydes,carboxylates, and esters), —CF₃, —CN and the like. Cycloalkyls can besubstituted in the same manner.

The terms “alkenyl” and “alkynyl”, refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The term “substituted alkenyl” refers to alkenyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

The term “substituted alkynyl” refers to alkynyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl,alkylaryl, haloalkyl, —CN, aryl, heteroaryl, and combinations thereof.

“Aryl,” as used herein, refers to C₅-C₂₆-membered aromatic, fusedaromatic, fused heterocyclic, or biaromatic ring systems. “Aryl,” asused herein, can include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and24-membered single-ring aromatic groups, for example, benzene,naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene,coronene, etc. “Aryl” further encompasses polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings (i.e., “fused rings”) wherein at least one of the ringsis aromatic, e.g., the other cyclic ring or rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocycles.

The term “substituted aryl” refers to an aryl group, wherein one or morehydrogen atoms on one or more aromatic rings are substituted with one ormore substituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (suchas a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl),silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate,or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate,phosphinate, amino (or quarternized amino), amido, amidine, imine,cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate,sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl(such as CF₃, —CH₂—CF₃, —CCl₃), —CN, aryl, heteroaryl, and combinationsthereof.

“Heterocycle,” “heterocyclic” and “heterocyclyl” are usedinterchangeably, and refer to a cyclic radical attached via a ringcarbon or nitrogen atom of a monocyclic or bicyclic ring containing 3-10ring atoms, and can have from 5-6 ring atoms, comprising carbon and oneto four heteroatoms each selected from the group consisting ofnon-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O,C₁-C₁₀ alkyl, phenyl or benzyl, and optionally containing 1-3 doublebonds and optionally substituted with one or more substituents.Heterocyclyl are distinguished from heteroaryl by definition. Examplesof heterocycles include, but are not limited to piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl,dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl,2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl,6H-1,2,5-thiadiazinyl. Heterocyclic groups can optionally be substitutedwith one or more substituents as defined above for alkyl and aryl.

The term “heteroaryl” refers to C₅-C₂₆-membered aromatic, fusedaromatic, biaromatic ring systems, or combinations thereof, in which oneor more carbon atoms on one or more aromatic ring structures have beensubstituted with a heteroatom. Suitable heteroatoms include, but are notlimited to, oxygen, sulfur, and nitrogen. Broadly defined, “heteroaryl,”as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and24-membered single-ring aromatic groups that may include from one tofour heteroatoms, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyridazine and pyrimidine, and the like. The heteroaryl group may alsobe referred to as “aryl heterocycles” or “heteroaromatics”. “Heteroaryl”further encompasses polycyclic ring systems having two or more rings inwhich two or more carbons are common to two adjoining rings (i.e.,“fused rings”) wherein at least one of the rings is heteroaromatic,e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heterocycles, or combinations thereof. Examples ofheteroaryl rings include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl,octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or moreof the rings can be substituted as defined below for “substitutedheteroaryl”.

The term “substituted heteroaryl” refers to a heteroaryl group in whichone or more hydrogen atoms on one or more heteroaromatic rings aresubstituted with one or more substituents including, but not limited to,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino,alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl (such as CF₃, —CH₂—CF₃, —CCl₃), —CN,aryl, heteroaryl, and combinations thereof.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Exemplary heteroatoms include nitrogen, oxygenand sulfur.

“Analog” and “Derivative” may be used interchangeably, and refer to acompound that possesses the same core as the parent compound, butdiffers from the parent compound in bond order, the absence or presenceof one or more atoms and/or groups of atoms, and combinations thereof.The derivative can differ from the parent compound, for example, in oneor more substituents present on the core, which may include one or moreatoms, functional groups, or substructures. In general, a derivative canbe imagined to be formed, at least theoretically, from the parentcompound via chemical and/or physical processes.

II. Compositions

A. Active Agents

Certain embodiments may comprise an active agent. An active agent maycomprise one or more of the following in various combinations as wouldbe understood by the skilled artisan.

An active agent comprising nicotinamide riboside and pterostilbene maybe administered to a patient in a therapeutically effective amount,producing the unexpectedly superior results of achieving a synergisticand positive, self-reinforcing effect between an NAD+ dependent sirtuinactivator compound (such as, but not limited to, pterostilbene) and NAD+precursor that can supplement NAD+ concentration (such as, but notlimited to, nicotinamide riboside). These effects may improve metabolicand mental health, thus reducing or eliminating certainneurodegenerative disorders and/or reducing, eliminating, orameliorating the indicia of neurodegenerative disorders. In someembodiments, a composition may comprise nicotinamide riboside andpterostilbene in a therapeutically effective amount and this compositioncan achieve the unexpectedly superior results of creating a positivefeedback loop as a result of cellular synergistic effects betweennicotinamide riboside and pterostilbene, thus SIRT1-activators such asbut not limited to pterostilbene could positively impact NAD+ productionand concomitantly activate SIRT2-6 in addition to activating SIRT1. Incertain embodiments as described herein, unexpectedly superior resultscan be achieved by providing optimal levels of sirtuin activity, whilesimultaneously normalizing any NAD+ deficiency.

Compositions as described herein can act as an agonist for peroxisomeproliferator-activated receptor alpha (PPAR-alpha). PPAR-alpha agonistscan exhibit neuroprotective benefits in animal models forneurodegenerative disorders such as but not limited to Parkinson'sdisease. Pterostilbene can demonstrate benefits in animal models forneurodegenerative disorders such as but not limited to Alzheimer'sdisease. Unexpectedly superior results may be achieved by providingpredetermined levels of sirtuin activity along with PPAR-alphaactivation as a result of administration of embodiments of compositionsas described herein.

B. Dietary Supplements

Certain embodiments may comprise a dietary supplement. A dietarysupplement may comprise one or more of the following in variouscombinations as would be understood by the skilled artisan.

A dietary supplement comprising nicotinamide riboside and/orpterostilbene in an effective amount may maintain normal or healthylevels of NAD+ concentration, maintain normal or healthy levels ofsirtuin activity, and/or maintain normal or healthy levels of cellulardetoxification in an individual. A dietary supplement comprisingnicotinamide riboside and/or pterostilbene may be administered to anindividual in an effective amount, producing the unexpectedly superiorresults of achieving a synergistic and positive, self-reinforcing effectbetween an NAD+ dependent sirtuin activator compound (such as, but notlimited to, pterostilbene) and NAD+ precursor that can supplement NAD+concentration (such as, but not limited to, nicotinamide riboside).These effects may reduce the risk of certain neurodegenerative disordersand/or reduce the risk of indicia of neurodegenerative disorders. Insome embodiments, a composition may comprise nicotinamide riboside andpterostilbene in an effective amount and this composition can achievethe unexpectedly superior results of creating a positive feedback loopas a result of cellular synergistic effects between nicotinamideriboside and pterostilbene, thus SIRT1-activators such as but notlimited to pterostilbene could positively impact NAD+ production andconcomitantly activate SIRT2-6 in addition to activating SIRT1. Incertain embodiments as described herein, unexpectedly superior resultscan be achieved by providing optimal levels of sirtuin activity, whilesimultaneously normalizing any NAD+ deficiency.

C. Nicotinamide Riboside

In certain embodiments, certain methods and compositions comprisenicotinamide riboside, a precursor of coenzyme NAD⁺, which is involvedin metabolic processes such as energy production, DNA repair, cellulardetoxification, the inflammatory response, and protein folding. Thechemical structure of nicotinamide riboside is provided below.

Nicotinamide riboside has four asymmetric centers and any opticalisomer, as separated, pure or partially purified optical isomers and anymixtures thereof including racemic mixtures can be used in embodimentsas described herein. The enantiomeric form can be in enantiomericexcess, e.g., essentially in a pure form. Accordingly, some embodimentscomprise nicotinamide riboside having an enantiomeric excess of at least60%, at least 70%, at least 80%, at least 85%, at least 90%, at least96%, at least 98%, and ranges therebetween.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. The compounds of embodiments of the inventionmay also be resolved by the formation of diastereomeric derivatives.Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jacques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981). Optically activecompounds can also be prepared from optically active starting materials.

Nicotinamide riboside can be a quaternary salt that can form an ionicbond with a counteranion. Examples of counteranions include the anionsof a suitable organic acid such as formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic,mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.Further examples of pharmaceutical acceptable inorganic or organic acidcounteranions comprise the salts listed in J. Pharm. Sci. 66, 2 (1977)),which is incorporated by reference In certain embodiments, an activeagent or a dietary supplement is a derivative, salt, solvate, or prodrugof nicotinamide riboside. In some embodiments, the riboside innicotinamide riboside is (3-D-ribose. In certain embodiments,nicotinamide riboside may be substituted or combined with nicotinamidemononucleotide, niacinamide, nicotinamide, nicotinic acid, and/orniacin.

In some embodiments, an active agent or a dietary supplement has achemical structure according to Formula I:

or is a pharmaceutically salt or acceptable salt thereof, wherein:

X is O, S, or NR;

R₁ and R₂ may be hydrogen, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a substituted or unsubstituted non-aromaticheterocyclic group or a substituted or unsubstituted aryl group;

R₃, R₄; R₅, R₆ and R₇ may be selected from the group consisting ofhydrogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted non-aromaticheterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′,—OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_(n)R, —S(O)_(n)OR,—S(O)_(n)NRR′, —NRR′, —NRC(O)OR′, —NO₂ and —NRC(O)R′;

R₈, R₁₀, and R₁₁ may be selected from the group consisting of hydrogen,a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(O)NRR′,—S(O)_(n)R, —S(O)_(n)OR, —S(O)_(n)NRR′, —C(S)R, —C(S)OR and —C(O)SR; and

R₉, R₁₂, and R₁₃, may be selected from the group consisting of hydrogen,a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted non-aromaticheterocyclic group, halogen, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′,—OC(O)NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_(n)R, —S(O)_(n)OR,—S(O)_(n)NRR′, —NRR′, —NRC(O)OR′, —NO₂ and —NRC(O)R′;

wherein R and R′ may be hydrogen, a substituted or unsubstituted alkylgroup, a substituted or unsubstituted aryl group or a substituted orunsubstituted non-aromatic heterocyclic group; and n is 1 or 2.Compounds of Formula I may include isomers, enantiomers, andstereoisomers thereof.

D. Pterostilbene

An active agent may comprise pterostilbene. A dietary supplement maycomprise pterostilbene. In certain embodiments, an active agent maycomprise nicotinamide riboside and pterostilbene. In certainembodiments, a dietary supplement may comprise nicotinamide riboside andpterostilbene.

The chemical structure of pterostilbene is provided below:

In some embodiments, an active agent or a dietary supplement comprises aderivative, salt, solvate, or prodrug of pterostilbene. In certainembodiments, pterostilbene may be substituted and/or combined withepsilon-viniferin and/or resveratrol.

In certain other embodiments, the active agent or a dietary supplementis a stilbene having a chemical structure according to Formula II:

or is a pharmaceutically acceptable salt or acceptable salt thereof,wherein:

R′₁, R′₂, and R′₃ may be hydrogen, a substituted or unsubstituted alkylgroup, a substituted or unsubstituted aryl group, —C(O)R, —C(O)OR,—C(O)NHR, —C(O)NRR′, —S(O)_(n)R, —S(O)_(n)OR, —S(O)_(n)NRR′, —C(S)R,—C(S)OR and —C(O)SR;

wherein R and R′ may be hydrogen, a substituted or unsubstituted alkylgroup, a substituted or unsubstituted aryl group or a substituted orunsubstituted non-aromatic heterocyclic group; and n is 1 or 2.Compounds of Formula II and Formula III may include isomers,enantiomers, and stereoisomers thereof.

E. Nicotinamide Mononucleotide

In certain embodiments, certain methods and compositions comprisenicotinamide mononucleotide, a precursor of coenzyme NAD⁺, which isinvolved in metabolic processes such as energy production, DNA repair,cellular detoxification, the inflammatory response, and protein folding.The chemical structure of nicotinamide mononucleotide is provided below.

Nicotinamide mononucleotide has four asymmetric centers and any opticalisomer, as separated, pure or partially purified optical isomers and anymixtures thereof including racemic mixtures can be used in embodimentsas described herein. The enantiomeric form can be in enantiomericexcess, e.g., essentially in a pure form. Accordingly, some embodimentscomprise nicotinamide riboside having an enantiomeric excess of at least60%, at least 70%, at least 80%, at least 85%, at least 90%, at least96%, at least 98%, and ranges there between.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. The compounds of embodiments of the inventionmay also be resolved by the formation of diastereomeric derivatives.Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jacques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981), which isincorporated by reference. Optically active compounds can also beprepared from optically active starting materials.

Nicotinamide mononucleotide can be a quaternary salt that can form anionic bond with a counteranion. Examples of counteranions include theanions of suitable organic acid such as formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic,mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.Further examples of acceptable inorganic or organic acid counteranionsinclude the salts listed in J. Pharm. Sci. 66, 2 (1977)), which isincorporated by reference. In certain embodiments, an active agent or adietary supplement is a derivative, salt, solvate, or prodrug ofnicotinamide mononucleotide. In certain embodiments, nicotinamidemononucleotide may be substituted or combined with nicotinamideriboside, niacinamide, nicotinamide, nicotinic acid, and/or niacin.

In some embodiments, an active agent or a dietary supplement has achemical structure according to Formula IV:

or is a pharmaceutically acceptable salt or acceptable salt thereof,wherein:

X is O, S, or NR; —R₁ and R₂ may be hydrogen, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkenyl group,a substituted or unsubstituted alkynyl group, a substituted orunsubstituted non-aromatic heterocyclic group or a substituted orunsubstituted aryl group;

R₃, R₄, R₅, R₆ and R₇ may be selected from the group consisting ofhydrogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted non-aromaticheterocyclic group, halogen, —OR, —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′,—OC(O)NRR′, —C(O)R, —COR, —SR, —OSO₃H, —S(O)_(n)R, —S(O)_(n)OR,—S(O)_(n)NRR′, —NRR′, —NRC(O)OR′, —NO₂ and —NRC(O)R′;

R₈ and R₁₀ may be selected from the group consisting of hydrogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaryl group, —C(O)R, —C(O)OR, —C(O)NHR, —C(O)NRR′, —S(O)_(n)R,—S(O)_(n)OR, —S(O)_(n)NRR′, —C(S)R, —C(S)OR and —C(O)SR;

R11 may be selected from the group consisting of hydrogen, a substitutedor unsubstituted alkyl group, a substituted or unsubstituted aryl group,—P(O)_(n), —P(O)_(n)R, —C(O)R, —C(O)OR, —C(O)NHR, —C(O)NRR′, —S(O)_(n)R,—S(O)_(n)OR, —S(O)_(n)NRR′, —C(S)R, —C(S)OR and —C(O)SR; and

R₉, R₁₂, and R₁₃, may be selected from the group consisting of hydrogen,a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted non-aromaticheterocyclic group, halogen. —CN, —CO₂R, —OCOR, —OCO₂R, —C(O)NRR′,—NRR′, —C(O)R, —COR, —OSO₃H, —S(O)_(n)R, —S(O)_(n)OR, —S(O)_(n)NRR′,—NRR′, —NRC(O)OR′, —NO₂ and —NRC(O)R′;

wherein R and R′ may be hydrogen, a substituted or unsubstituted alkylgroup, a substituted or unsubstituted aryl group or a substituted orunsubstituted non-aromatic heterocyclic group; and n is 1 or 2.Compounds of Formula IV may include isomers, enantiomers, andstereoisomers thereof.

F. Routes of Administration

In some embodiments, compounds, compositions, dietary supplements,and/or pharmaceutical compositions as described herein are formulatedfor oral delivery, i.e., in a formulation such as an oral formulation.Oral solid dosage forms are described generally in Remington'sPharmaceutical Sciences, 18^(th) Ed. 1990 (Mack Publishing Co. EastonPa. 18042) at Chapter 89, which is incorporated by reference in itsentirety. Solid dosage forms comprise tablets, capsules, pills, trochesor lozenges, cachets, pellets, powders, or granules or incorporation ofthe material into particulate preparations of polymeric compounds suchas polylactic acid, polyglycolic acid, etc., or into liposomes. Suchcompositions may influence the physical state, stability, rate of invivo release, and rate of in vivo clearance of the disclosed. See, e.g.,Remington's Pharmaceutical Sciences, 18^(th) Ed. (1990, Mack PublishingCo., Easton, Pa. 18042) pages 1435-1712, which in its entirety isincorporated by reference. Compositions of some embodiments may beprepared in liquid form, or may be in dried powder (e.g., lyophilized)form. Liposomal or proteinoid encapsulation may be used to formulatecompositions as described herein. Liposomal encapsulation may be usedand the liposomes may be derivatized with various polymers (e.g., U.S.Pat. No. 5,013,556, which is incorporated by reference). See also,Marshall, K. In: Modern Pharmaceutics Edited by G. S. Banker and C. T.Rhodes Chapter 10, 1979, which is incorporated by reference. Aformulation may include a peptide (or chemically modified forms thereof)and inert ingredients that protect compounds in the stomach environment,and release of an active agent or a dietary supplement in the intestine.

Nicotinamide riboside, niacinamide, nicotinamide, nicotinic acid,pterostilbene, nicotinamide mononucleotide, niacin, epsilon-viniferin,resveratrol or derivatives thereof may be chemically modified so thatoral delivery of an embodiment of the compound is therapeuticallyefficacious or efficacious to achieve a desired result as a dietarysupplement. Contemplated chemical modification is the attachment of atleast one moiety to the component molecule itself, where the moietypermits uptake into the blood stream from the stomach or intestine, oruptake directly into the intestinal mucosa. Also contemplated is theincrease in overall stability of embodiments of the compositionsdescribed herein and increase in circulation time in the body. Certainembodiments may be pharmaceutical compositions. Certain embodiments maybe dietary supplements.

Certain embodiments provide liquid dosage forms for oral administration,including pharmaceutically acceptable emulsions, solutions, suspensions,and syrups, which may contain other components including inert diluents;adjuvants such as wetting agents, emulsifying and suspending agents; andsweetening, and flavoring agents. Certain embodiments provide liquiddosage forms for oral administration, including acceptable emulsions,solutions, suspensions, and syrups, which may contain other componentsincluding inert diluents; adjuvants such as wetting agents, emulsifyingand suspending agents; and sweetening, and flavoring agents suitable foruse in dietary supplements.

Controlled release oral formulations may be provided in someembodiments. Controlled release may include, but is not limited to,delayed release and pH-dependent release. In certain embodiments,compositions as described herein, or derivatives thereof can beincorporated into microcapsules, microparticulates, nanoparticulates,etc. through use of release-altering agents such as coatings to affectrelease of at least one active agent. In certain embodiments,compositions as described herein, or derivatives thereof can beincorporated into an inert matrix which permits release by eitherdiffusion or leaching mechanisms, e.g., gums. Slowly degeneratingmatrices may also be incorporated into compositions as described herein.

Modified release oral formulations may be provided. Modified release mayallow for specific release profiles.

Extended release oral formulations may be provided. Extended release mayallow for release of an active agent or dietary supplement over adesired time period.

Additional discussions for varying release formulations and relatedterms may be found in Lesczek Krowczynski, Extended-Release DosageForms, 1987 (CRC Press, Inc.), which is incorporated by reference.

In certain embodiments, the form of a controlled, modified or extendedrelease oral formulation is a tablet, capsule, or microbeads for oraladministration. In other aspects, controlled, modified or extendedrelease formulations comprising suitable and effect treatment amounts ofthe desired components may be pills, powders, granules, sterileparenteral solutions or suspensions, oral solutions or suspensions, oilwater emulsions as well as implants and microencapsulated deliverysystems.

Embodiments of some formulations may provide controlled, modified orextended release profiles. Compositions of embodiments of the presentinvention may comprise a conventional binder, excipients and additives,which may act to control, modify or extend release when used insufficient quantities. Certain embodiments comprise a pharmaceuticalbinder, excipient, and/or additive, which may act to control, modify orextend release when used in sufficient quantities. Coating agents, e.g.,plasticizers, may be used to enhance the controlled, modified orextended release features of embodiments of compositions of theinvention.

For oral formulations, the location of release may be the stomach, thesmall intestine (the duodenum, the jejunum, or the ileum), or the largeintestine. Such a release can avoid the deleterious effects of thestomach environment, either by protection of at least one active agent(or derivative) or by release of at least one active agent or dietarysupplement (or derivative) beyond the stomach environment, such as inthe intestine. To ensure full gastric resistance a coating temporallyimpermeable to at least pH 5.0 is useful in some embodiments. Examplesof some inert ingredients that are used as enteric coatings arecellulose acetate trimellitate (CAT), hydroxypropylmethylcellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), poly(methacrylicacid-co-ethyl acrylate) 1:1, cellulose acetate phthalate (CAP),poly(methacylic acid-co-methyl methacrylate) 1:1, poly(methacylicacid-co-methyl methacrylate) 1:2, and natural shellac resin. In someembodiments, coatings may be used as mixed films.

i. Soft or Hard Gel Capsules

Certain embodiments utilize oral administration of soft capsulescomprising nicotinamide riboside and/or pterostilbene or embodiments ofcompositions as described herein. Some embodiments of methods compriseadministering a capsule comprising an effective amount of nicotinamideriboside and/or pterostilbene, or embodiments of compositions asdescribed herein. A capsule can be a hard capsule or a soft capsule. Asoft capsule can be prepared using techniques well known in the art. Forexample, soft capsules can be produced using a rotary die encapsulationprocess. Active agent or dietary supplement formulations can be fed intoan encapsulation machine by gravity. In some embodiments, a formulationcomprises pharmaceutical and/or dietary supplement excipients such asolive oil, gelatin, glycerin, purified water, beeswax yellow, sunflowerlecithin, silicon dioxide, titanium dioxide, F. D. & C Blue 1 and F. D.& C Red 4, microcrystalline cellulose, hypromellose, vegetable magnesiumstearate, and/or silica.

A capsule shell can comprise one or more plasticizers such as glycerin,sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol,polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters,triethyl citrate and combinations thereof. In some embodiments, aplasticizer can be glycerin.

In addition to plasticizer(s), a capsule shell can comprise othersuitable shell additives such as opacifiers, colorants, humectants,preservatives, flavorings, and buffering salts and acids.

Opacifiers can be used to opacify a capsule shell when an encapsulatedactive agent(s) is light sensitive. Suitable opacifiers include, but notlimited to, titanium dioxide, zinc oxide, calcium carbonate andcombinations thereof. In some embodiments, the opacifier can be titaniumdioxide.

Colorants can be used to for marketing and product identification and/ordifferentiation purposes. Suitable colorants include synthetic andnatural dyes and combinations thereof.

Humectants can be used to suppress the water activity of a softgel.Suitable humectants include but are not limited to glycerin andsorbitol, which can be components of a plasticizer composition. Due tothe low water activity of dried, properly stored softgels, the greatestrisk from microorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into some embodiments of a capsuleshell. Suitable preservatives include but are not limited to alkylesters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyland heptyl (collectively known as “parabens”) or combinations thereof.

In certain embodiments, a composition comprises nicotinamide ribosideand pterostilbene as active agents or dietary supplements. Someembodiments can be in a capsule formed of microcrystalline cellulose,hypromellose, vegetable magnesium stearate, olive oil, gelatin,glycerin, purified water, beeswax yellow, sunflower lecithin, silicondioxide, titanium dioxide, F. D. & C Blue 1 and F. D. & C Red 4, orvegetarian hard capsules made solely of plant materials. Any embodimentas described herein may include microcrystalline cellulose,hypromellose, vegetable magnesium stearate, and/or silica.

Other excipients (which can be pharmaceutical excipients in someembodiments) that can be included in the disclosed formulations, includeacetyl-L-carnitine, N-acetyl cysteine, α-lipoic acid, biotin, thiamine,pantothenic acid, vitamin B6, vitamin B12, vitamin K, taurine, folicacid, resveratrol, vinpocetine, chromium picolinate, vitamin C, vitaminD3, vitamin E, vinaringin, quercetin, curcumin, coenzyme Q, creatine andsalts thereof.

ii. Solutions and Suspensions

Certain embodiments can comprise a composition administered as a liquidwith an active agent or a dietary supplement dissolved (e.g., solution)or dispersed (e.g., suspension) in the composition. The solution orsuspension may be prepared using one or more acceptable excipient and/orpharmaceutically acceptable excipients. Suitable excipients include, butare not limited to, surfactants, humectants, plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,solubilizers, bioavailability enhancers, pH adjusting agents, flavorantsand combinations.

iii. Controlled Delivery Polymeric Matrices

Controlled release polymeric devices can be made for long term releasesystemically following implantation of a polymeric device (rod,cylinder, film, disk), injection or oral ingestion (microparticles). Apolymeric device matrix can be in the form of microparticles such asmicrospheres, where peptides can be dispersed within a solid polymericmatrix or microcapsules, where the core can be of a different materialthan the polymeric shell, and the peptide can be dispersed or suspendedin the core, which may be liquid or solid in nature. Unless specificallydefined herein, microparticles, microspheres, and microcapsules can beused interchangeably. A polymer matrix may be cast as a thin slab orfilm, ranging from nanometers to four centimeters, a powder produced bygrinding or other standard techniques, or even a gel such as a hydrogel.

Non-biodegradable or biodegradable matrices can be used for delivery ofdisclosed compounds, although biodegradable matrices are present incertain embodiments. These may be natural or synthetic polymers,although synthetic polymers may be used in certain embodiments forcharacterization of degradation and release profiles. A polymer can beselected based on the period over which release is desired. In somecases linear release may be most useful, although in others a pulserelease or “bulk release” may provide more effective results. In certainembodiments, the polymer may be in the form of a hydrogel (typically inabsorbing up to about 90% by weight of water), and can optionally becrosslinked with multivalent ions or polymers.

Polymeric device matrices can be formed by solvent evaporation, spraydrying, solvent extraction and other methods known to those skilled inthe art. Bioerodible microspheres can be prepared using any of themethods developed for making microspheres for drug delivery (which canalso be used for dietary supplements), for example, as described byMathiowitz and Langer, J. Controlled Release 5:13-22 (1987); Mathiowitz,et al., Reactive Polymers 6:275-283 (1987); and Mathiowitz, et al., J.Appl. Polymer Sci. 35:755-774 (1988) both of which are incorporated byreference in their entirety.

Polymeric devices can be formulated for local release to treat the areaof implantation or injection—which can deliver a dosage that is muchless than the dosage for treatment of an entire body—or systemicdelivery. Some of these embodiments can be implanted or injectedsubcutaneously, into the muscle, fat, or swallowed.

G. Dosages and Dosage Regiments

Selection of embodiments of a particular therapeutically effective doseor an effective dose can be determined (e.g. but not limited to, viaclinical trials) by a skilled artisan based upon the consideration ofseveral factors which will be known to one of skill in the art. Suchfactors include the disorder to be treated, prevented, reduction ofindicia of neurodegenerative disorders, the symptoms involved, thesubject's body mass, the subject's age, the subject's immune status andother factors known by the skilled artisan. The precise dose to beemployed in the formulation will also depend on the route ofadministration, and the seriousness of the disorder-related wasting, andshould be decided according to the judgment of the skilled artisan andeach subject's circumstances. Effective doses can be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

The dose of the active agent or the dietary supplement to beadministered to a subject, such as a human, can be variable and can besubject to independent judgment. It is often practical to administer thedaily dose of the active agent or dietary supplement at various hours ofthe day. The amount of the active agent or dietary supplementadministered may depend on such factors as the solubility of the activeagent or dietary supplement, the formulation used, subject condition(such as weight), and/or the route of administration. In certainembodiments, a dose of administered nicotinamide riboside or itsequivalents, alone or in combination with pterostilbene or itsequivalents is administered orally.

Effective amounts of administered nicotinamide riboside or itsequivalents, alone or in combination with pterostilbene or itsequivalents, can be in an amount of between about 50 mg and about 1500mg, between about 100 mg and about 1500 mg, between about 100 mg andabout 1000 mg per day, between about 125 mg and about 900 mg per day,between about 150 mg and about 850 mg per day, between about 200 mg to700 mg per day, between about 200 mg to about 500 mg per day, about 250mg per day, between about 1000 mg and about 1500 mg, or 250 mg per day.In certain embodiments, an effective amount of nicotinamide riboside orits equivalents may be administered via multiple doses.

An effective amount of administered pterostilbene or its equivalents,alone or in combination with nicotinamide riboside or its equivalents,can be in an amount between about 25 mg and about 1000 mg, between about100 mg and about 1000 mg, between about 25 mg and about 500 mg per day,between about 25 mg and about 250 mg per day, between about 30 mg andabout 225 mg per day, between about 40 mg and about 200 mg per day,between about 45 mg and about 250 mg per day, about 50 mg per day, orabout 50 mg per day. In certain embodiments, an effective amount ofpterostilbene or its equivalents may be administer via multiple doses.In an embodiment, the compounds, compositions, dietary supplements, orpharmaceutical compositions containing nicotinamide riboside andpterostilbene are prepared as oral formulations.

In certain embodiments a composition may be administered in a dosageregimen over days, weeks, or months. Dosages may be multiple times perday or singular doses per day. Each dosage when dosages are administeredover multiple days, weeks, or months may or may not be equal amounts.Dosage amounts during a dosage regimen may vary according to the amountsand ranges disclosed herein. A dosage may comprise administeringnicotinamide riboside alone or in combination with pterostilbene. Adosage may comprise administering pterostilbene alone or in combinationwith nicotinamide riboside.

In certain embodiments, a composition as disclosed herein can beadministered intravenously, intraperitoneally, subcutaneously,intramuscularly, intrathecally, sublingually, into the buccal cavity,rectally, or by aerosol.

III. Methods of Use

Certain compositions and methods described herein may have beneficialeffects on symptoms associated with neurodegenerative disorders. Certaincompositions and methods described herein may treat and/or preventneurodegenerative disorders. Certain compositions may maintain normal orhealthy levels of indicia of neurodegenerative disorders. Certaincompositions may reduce the risk of developing indicia ofneurodegenerative disorders. Certain compositions may reduce the risk ofindicia of neurodegenerative disorders. Certain compositions describedherein may be oral compositions to provide oral formulations fortreating and/or preventing neurodegenerative disorders. Certaincompositions and methods described herein may improve and/or maintain anaesthetic appearance of neurodegenerative disorder. In some embodiments,a composition may treat and/or prevent a neurodegenerative disorder.Some embodiments may be a pharmaceutical ingredient and others may be adietary supplement.

Neurodegenerative disorders that can be treated include, but are notlimited to, those associated with aging, Parkinson's disease,Alzheimer's disease, dementia, and diabetes. A dietary supplement mayreduce the risk of developing indicia of these neurodegenerativedisorders. Neurodegenerative disorders that are treated may or may notexclude those associated with aging, Parkinson's disease, Alzheimer'sdisease, Huntington's disease, and dementia, as will be indicated in theclaims.

In some embodiments, a neurodegenerative disorder treated withembodiments of the described compositions and methods include, but arenot limited to Parkinson's disease, Alzheimer's disease, andHuntington's disease.

In certain embodiments, a composition as described herein can be used toreduce dosage levels of dopamine agonists, monoamine oxidase inhibitors,and/or levodopa and the like. Other medications administered to apatient having Parkinson's disease that can have dosage levels reducedwould be readily ascertainable to the skilled artisan. In certainembodiments, compositions as described herein can be administered to apatient to treat Parkinson's disease. In certain embodiments,compositions as described herein can be administered to a patient totreat indicia of Parkinson's disease. In certain embodiments,compositions as described herein may be administered to increaseactivation of heat shock factor 1.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1: Exemplary Composition

Materials: One Composition is the Product Marketed by Elysium Health as“BASIS®”.

TABLE 1 Active Components of BASIS ® Component Weight of componentNicotinamide riboside 250 mg Pterostilbene 50 mg

BASIS® may further contain the following excipients: microcrystallinecellulose, hypromellose, vegetable magnesium stearate, olive oil,gelatin, glycerin, purified water, beeswax yellow, sunflower lecithin,silicon dioxide, titanium dioxide, F. D. & C Blue 1 and F. D. & C Red 4.Any embodiment may include microcrystalline cellulose, hypromellose,vegetable magnesium stearate, and/or silica.

Example 2: Mouse Model

In an embodiment, Parkinson's model mice (e.g., mice systemicallyinjected with 1-methyl 4-phenyltetrahydropyridine (MPTP)) will be usedand will be treated using the following treatments:

The test mice will be broken into four groups:

1. Control (no treatment);

2. Treatment with nicotinamide riboside (NR), nicotinamidemononucleotide (NMN) and combinations thereof;

3. Treatment with NR, NMN, pterostilbene, and combinations thereof;

4. Pterostilbene treated;

5. Mice treated with NR, NMN and combinations thereof, and pterostilbene

Mice will be treated daily for three weeks, and specific assays will becarried out to determine whether indicia of neurodegenerative disordershave been improved. These assays will include, but not be limited to,testing mouse sensorimotor function including but not limited to,neurochemical assay of using tyrosine hydroxylase, behavioral testingsuch as rotational bias, testing of motor functions such as turningability and reaching ability, testing sensory stimuli, responses tolight, and the like.

For this example, the viability of the dopaminergic neurons will bescored by staining appropriate brain sections for tyrosine hydroxylase.

Doses of NR and NMN will be about 250 mg/kg body weight of mice/daily.Doses of pterostilbene will be about 100 mg/kg body weight ofmice/daily. Doses of NR, NMN and combinations thereof, and pterostilbenewill be about 250 mg/kg body weight of mice/daily. NR, NMN,pterostilbene and combinations thereof will be administered byintraperitoneal (IP) injection or by supplementing the food or thewater.

Example 3: Transgenic Mouse Model

In an embodiment, a transgenic mouse model (e.g., alpha synucleintransgenic mice) will be used and will be treated using the followingtreatments:

The test mice will be broken into four groups:

1. Control (no treatment);

2. Treatment with nicotinamide riboside (NR), nicotinamidemononucleotide (NMN) and combinations thereof;

3. Treatment with NR, NMN, pterostilbene, and combinations thereof;

4. Pterostilbene treated;

5. Mice treated with NR, NMN and combinations thereof, and pterostilbene

Mice will be treated daily for three weeks, and specific assays will becarried out to determine whether indicia of neurodegenerative disordershave been improved. These assays will include, but not be limited to,testing mouse sensorimotor function including but not limited to,neurochemical assay of using tyrosine hydroxylase, behavioral testingsuch as rotational bias, testing of motor functions such as turningability and reaching ability, testing sensory stimuli, responses tolight, and the like.

For these transgenic mice, measured endpoints will be survival rates ofthe treated transgenic mice that will be compared to untreatedtransgenic mice (i.e., Tg/Tg mice typically live about 6 months), andassays will be conducted to test for physical strength and dexterity,such as on a rotarod and/or treadmill.

Doses of NR and NMN will be about 250 mg/kg body weight of mice/daily.Doses of pterostilbene will be about 100 mg/kg body weight ofmice/daily. Doses of NR, NMN and combinations thereof, and pterostilbenewill be about 250 mg/kg body weight of mice/daily. NR, NMN,pterostilbene and combinations thereof will be administered byintraperitoneal (IP) injection or by supplementing the food or thewater.

Example 4: Results of Human Administration

In an embodiment, human subjects will be given a dosage of about 500mg/day of NR and/or NMN. Human subjects may also be given about 100mg/day of pterostilbene. Some subjects will be given a dose 500 mgnicotinamide riboside and 100 mg of pterostilbene for 60 days for thetreatment of indicia of Parkinson's disease. Subjects are to be groupedbased upon certain indicia of neurodegenerative disorders, such asParkinson's disease. Several of the symptoms described herein will bemonitored and their indicia will be improved. Each participant will alsoself-report using a survey that will contain questions related toindicia of symptoms of a neurodegenerative disorder. The trial will beplacebo-controlled, randomized and blinded.

A reduction in the indicia of Parkinson's disease will be observed. Areduction in Parkinson's disease medication L-DOPA will be reduced.Subjects will also be tested to see responses in tremor reduction,increases in mental cognition, memory increase, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe material for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

Although the foregoing description is directed to preferred embodimentsof the invention, it is noted that other variations and modificationswill be apparent to those skilled in the art, and may be made withoutdeparting from the spirit or scope of the invention. Moreover, featuresdescribed in connection with one embodiment of the invention may be usedin conjunction with other embodiments, even if not explicitly statedabove.

We claim:
 1. A method of reducing the prevalence of indicia of aneurodegenerative disease in a subject in need thereof comprisingadministering to the subject a composition consisting of nicotinamideriboside, pterostilbene and a pharmaceutically acceptable carrier and/orexcipient, wherein the composition is administered to the subject daily,and the daily dose of nicotinamide riboside is between 200 mg to 700 mgand the daily dose of pterostilbene is between 45 mg to 250 mg.
 2. Themethod of claim 1, wherein the indicia of a neurodegenerative diseaseare tremors, resting tremors, bradykinesia, NAD+ content, sirtuinactivity, limb rigidity, Lewy bodies, postural instability, freezing ofgait, micrographia, reduced facial expression, uncontrolled movements,movement that is abnormally fast or slow, stooped posture, dystonia,impaired fine motor dexterity, impaired motor coordination, impairedgross motor coordination, decreased arm swing, akathisia, speechproblems, softness of voice or slurred speech, difficulty swallowing,sexual dysfunction, cramping, drooling, excess saliva, loss of sense ofsmell, constipation, rapid eye movement (REM) behavior disorder, mooddisorder, orthostatic hypotension, sleep disturbances, vision problems,fatigue, loss of energy, depression, memory issues, slowed thinking,confusion, death of dopaminergic neurons, reduced dopamineconcentration, prion occurrence, or dementia.
 3. The method of claim 1,wherein the neurodegenerative disease is Alzheimer's disease,Parkinson's disease, or Huntington's disease.
 4. The method of claim 1,wherein the administration of the composition comprises administeringone or more doses of the composition.
 5. The method of claim 4, whereintwo or more, thirty or more, fifty or more, or one hundred or more dosesof the composition are administered.
 6. The method of claim 4, whereinthe doses are administered for at least 7 days, at least 30 days, atleast 60 days, at least 90 days, or at least six months.
 7. The methodof claim 1, wherein the composition is formulated as a pill, a tablet,or a capsule.
 8. The method of claim 1, wherein the composition isadministered orally.
 9. The method of claim 1, wherein the compositionis self-administered.
 10. A method of reducing the prevalence of indiciaof a neurodegenerative disease in a subject in need thereof comprisingadministering to the subject a composition consisting of nicotinamideriboside, pterostilbene and a pharmaceutically acceptable carrier orexcipient, wherein the composition is administered to the subject daily,and the daily dose of nicotinamide riboside is 500 mg and the daily doseof pterostilbene is 100 mg.